tbuckley/cabot-search huggingface dataset:
Invitation strategies and participation in a community-based lung cancer screening programme located in areas of high socioeconomic deprivation
Authors: Patrick Goodley, Haval Balata, Alberto Alonso, Christopher Brockelsby, Matthew Conroy, Nicola Cooper-Moss, Christopher Craig, Matthew Evison, Kath Hewitt, Coral Higgins, William Johnson, Judith Lyons, Zoe Merchant, Ailsa Rowlands, Anna Sharman, Nicola Sinnott, Matthew Sperrin, Richard Booton, Philip A J Crosbie
Journal: Thorax (2023)

Introduction Although lung cancer screening is being implemented in the UK, there is uncertainty about the optimal invitation strategy. Here, we report participation in a community screening programme following a population-based invitation approach, examine factors associated with participation, and compare outcomes with hypothetical targeted invitations. Methods Letters were sent to all individuals (age 55–80) registered with a general practice (n=35 practices) in North and East Manchester, inviting ever-smokers to attend a Lung Health Check (LHC). Attendees at higher risk (PLCO m2012NoRace score≥1.5%) were offered two rounds of annual low-dose CT screening. Primary care recorded smoking codes (live and historical) were used to model hypothetical targeted invitation approaches for comparison. Results Letters were sent to 35 899 individuals, 71% from the most socioeconomically deprived quintile. Estimated response rate in ever-smokers was 49%; a lower response rate was associated with younger age, male sex, and primary care recorded current smoking status ( adj OR 0.55 (95% CI 0.52 to 0.58), p&lt;0.001). 83% of eligible respondents attended an LHC (n=8887/10 708). 51% were eligible for screening (n=4540/8887) of whom 98% had a baseline scan (n=4468/4540). Screening adherence was 83% (n=3488/4199) and lung cancer detection 3.2% (n=144) over 2 rounds. Modelled targeted approaches required 32%–48% fewer invitations, identified 94.6%–99.3% individuals eligible for screening, and included 97.1%–98.6% of screen-detected lung cancers. Discussion Using a population-based invitation strategy, in an area of high socioeconomic deprivation, is effective and may increase screening accessibility. Due to limitations in primary care records, targeted approaches should incorporate historical smoking codes and individuals with absent smoking records.
Flashback Foreword: Chemoradiotherapy for Nasopharyngeal Carcinoma
Authors: Maura L. Gillison
Journal: Journal of Clinical Oncology (2023)

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.. August 16, 2023 ARTICLE CITATION DOI: 10.1200/JCO.23.00932 Journal of Clinical Oncology - published online before print August 16, 2023 PMID: 37586208 Flashback Foreword: Chemoradiotherapy for Nasopharyngeal Carcinoma Maura L. Gillison, MD, PhD1,2xMaura L. GillisonSearch for articles by this author Show More 1Associate Editor, Journal of Clinical Oncology, Alexandria, VA2MD Anderson, Houston, TX https://doi.org/10.1200/JCO.23.00932 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 1998, Al-Sarraf et al1 reported significant improvements in overall and progression-free survival for patients with locoregionally advanced nasopharyngeal carcinoma when concurrent and adjuvant cisplatin-based chemotherapy was added to radiation therapy. The trial immediately changed the standard of care but raised numerous questions regarding the relative contributions of concurrent versus adjuvant chemotherapy.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Chemoradiotherapy for Nasopharyngeal CarcinomaThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Maura L. GillisonThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Bristol Myers Squibb, Merck, EMD Serono, BioNTech, Shattuck Labs, Bayer, Debiopharm Group, Ipsen, Gilead Sciences, Bicara Therapeutics, BioNTech, Nektar, Istari, LLX Solutions, OncLive, Seagen, Kura Oncology, Mirati Therapeutics, Sensei Biotherapeutics, Eisai, Exelixis, ITeos Therapeutics, Caladrius Biosciences, Coherus BiosciencesResearch Funding: Bristol Myers Squibb (Inst), Genocea Biosciences (Inst), Cullinan Oncology (Inst), Genentech (Inst), Agenus (Inst), Kura Oncology (Inst), Seagen (Inst)No other potential conflicts of interest were reported. Companion Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
Authors: M Al-Sarraf, M LeBlanc, P G Giri, K K Fu, J Cooper, T Vuong, A A Forastiere, G Adams, W A Sakr, D E Schuller, J F Ensley
Journal: Journal of Clinical Oncology (2023)

PURPOSE The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P &lt; .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P &lt; .001). CONCLUSION We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.
Non-pharmacological and pharmacological interventions for the reduction or prevention of topographies of behaviours that challenge in people with intellectual disabilities: a systematic review and meta-analysis of randomised controlled trials
Authors: Laura Groves, Chris Jones, Alice Welham, Anna Hamilton, Ashley Liew, Caroline Richards
Journal: The Lancet Psychiatry (2023)

BackgroundPeople with intellectual disability show a high prevalence of behaviours that challenge. Clinical guidelines recommend that such behaviour should first be treated with non-pharmacological interventions, but research suggests off-label pharmaceuticals are commonly used. We aimed to evaluate the efficacy of non-pharmacological and pharmacological interventions for topographies of behaviours that challenge drawn from randomised controlled trials (RCTs).MethodsIn this systematic review and meta-analysis, we searched PsycINFO, MEDLINE, Embase, CINAHL, and CENTRAL databases for RCT studies assessing an intervention (pharmacological or non-pharmacological) for behaviours that challenge (self-injury behaviour, aggression, destruction of property, irritability, and a composite overall measure) in participants with intellectual disability. The primary aim was to assess the efficacy of non-pharmacological and pharmacological interventions on behaviours that challenge. Secondary aims were to evaluate how effects varied over time and whether intervention, methodological, and participant characteristics moderate efficacy. We extracted standard mean difference (SMD) effect sizes (Cohen's d) from eligible studies and meta-analysed the data using a series of random effects models and subgroup analyses. This study was registered with PROSPERO 2021, CRD4202124997.FindingsOf 11 912 reports identified, 82 studies were included. 42 (51%) studies assessed non-pharmacological interventions and 40 (49%) assessed pharmacological interventions. Across all studies, 4637 people with intellectual disability aged 1–84 years (mean age 17·2 years) were included. 2873 (68·2%) were male, 1339 (28·9%) were female, and for 425 (9·2%) individuals, data on gender were not available. Data on ethnicity were unavailable. Small intervention effects were found for overall behaviours that challenge at post-intervention (SMD –0·422, 95% CI –0·565 to –0·279), overall behaviours that challenge at follow-up (–0·324, –0·551 to –0·097), self-injury behaviour at post-intervention (–0·238, –0·453 to –0·023), aggression at post-intervention (–0·438, –0·566 to –0·309), and irritability at post-intervention (–0·255, –0·484 to –0·026). No significant differences between non-pharmacological and pharmacological interventions were found for any topography of behaviours that challenge (all p>0·05).InterpretationA broad range of interventions for behaviours that challenge are efficacious with small effect sizes for people with intellectual disability. These findings highlight the importance of precision in the measurement of behaviours that challenge, and when operationalising intervention components and dosages.FundingCerebra.
Contributions of joint damage-related events to gout pathogenesis: new insights from laboratory research
Authors: HanLin Xu, Hengwei Qin, YingHui Hua, Nicola Dalbeth
Journal: Annals of the Rheumatic Diseases (2023)

Epidemiological and imaging findings indicate that gout frequently affects damaged joints. Recent studies suggest that the relationship between gout and joint damage may be more complex than a simple unidirectional link and that joint damage may promote the development of gout at affected sites. In this article, we review the clinical associations and recent laboratory research identifying events in the setting of osteoarthritis or joint injury that can alter the intraarticular microenvironment and locally regulate monosodium urate crystallisation and deposition or amplify the inflammatory response to deposited crystals. This includes cartilage matrix proteins or fibres released into the articular space that accelerates the crystallisation process, as well as the lack of lubricin and fibroblast priming that enhances the immune response towards the deposited crystals. These findings provide new insights into gout pathogenesis and offer a possible explanation for the site preference of gout in the damaged joint.
TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy
Authors: Siri Amanda Tvingsholm, Marcus Svensson Frej, Vibeke Mindahl Rafa, Ulla Kring Hansen, Maria Ormhøj, Alexander Tyron, Agnete W P Jensen, Mohammad Kadivar, Amalie Kai Bentzen, Kamilla K Munk, Gitte N Aasbjerg, Jeppe S H Ternander, Christina Heeke, Tripti Tamhane, Christian Schmess, Samuel A. Funt, Julie Westerlin Kjeldsen, Anders Handrup Kverneland, Özcan Met, Arianna Draghi, Søren Nyboe Jakobsen, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
Journal: Journal for ImmunoTherapy of Cancer (2023)

Adoptive cell therapy (ACT) has shown promising results for the treatment of cancer and viral infections. Successful ACT relies on ex vivo expansion of large numbers of desired T-cells with strong cytotoxic capacity and in vivo persistence, which constitutes the greatest challenge to current ACT strategies. Here, in this study, we present a novel technology for ex vivo expansion of antigen-specific T-cells; artificial antigen-presenting scaffolds (Ag-scaffolds) consisting of a dextran-polysaccharide backbone, decorated with combinations of peptide-Major Histocompatibility Complex (pMHC), cytokines and co-stimulatory molecules, enabling coordinated stimulation of antigen-specific T-cells. The capacity of Ag-scaffolds to expand antigen-specific T-cells was explored in ex vivo cultures with peripheral blood mononuclear cells from healthy donors and patients with metastatic melanoma. The resulting T-cell products were assessed for phenotypic and functional characteristics. We identified an optimal Ag-scaffold for expansion of T-cells for ACT, carrying pMHC and interleukin-2 (IL-2) and IL-21, with which we efficiently expanded both virus-specific and tumor-specific CD8+ T cells from peripheral blood of healthy donors and patients, respectively. The resulting T-cell products were characterized by a high frequency of antigen-specific cells with high self-renewal capacity, low exhaustion, a multifunctional cytokine profile upon antigen-challenge and superior tumor killing capacity. This demonstrates that the coordinated stimuli provided by an optimized stoichiometry of TCR engaging (pMHC) and stimulatory (cytokine) moieties is essential to obtain desired T-cell characteristics. To generate an 'off-the-shelf' multitargeting Ag-scaffold product of relevance to patients with metastatic melanoma, we identified the 30 most frequently recognized shared HLA-A0201-restricted melanoma epitopes in a cohort of 87 patients. By combining these in an Ag-scaffold product, we were able to expand tumor-specific T-cells from 60-70% of patients with melanoma, yielding a multitargeted T-cell product with up to 25% specific and phenotypically and functionally improved T cells. Taken together, the Ag-scaffold represents a promising new technology for selective expansion of antigen-specific CD8+ T cells directly from blood, yielding a highly specific and functionally enhanced T-cell product for ACT.
Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Authors: David A Schoenfeld, Myrto Moutafi, Sandra Martinez, Dijana Djureinovic, Ross D Merkin, Adebowale Adeniran, David A Braun, Sabina Signoretti, Toni K Choueiri, Fabio Parisi, Michael Hurwitz, David L Rimm, Wei Wei, Lucia Jilaveanu, Harriet M Kluger
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized. Methods We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases. Results We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation. Conclusions Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.
Author Correction: Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer
Authors: Sergio Serrano-Villar, Camilla Tincati, Sajan C. Raju, Johan S. Sáenz, Elena Moreno, Rafael Bargiela, Alfonso Cabello-Ubeda, Elena Sendagorta, Alina Kurz, Jose A. Perez Molina, Amparo de Benito, Johannes R. Hov, Laura Fernandez-Lopez, Alfonso Muriel, Rosa del Campo, Santiago Moreno, Marius Trøseid, Jana Seifert, Manuel Ferrer
Journal: Nature Medicine (2023)
Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia
Authors: Theresa Eifert, Chen-Jen Hsu, Alicia L. Becker, Sarah Graessle, Arik Horne, Franziska Bemmann, Qirui Zhang, Michael Heuser, Valeri Vasioukhin, Sebastian Scholl, Andreas Hochhaus, Florian Siegerist, Nicole Endlich, Lars Bullinger, Steven W. Lane, Simon Haas, Tina M. Schnoeder, Florian H. Heidel
Journal: Leukemia (2023)

Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members are conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Inactivation of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.
Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice
Authors: Cana Park, Oliver Hahn, Shweta Gupta, Arturo J. Moreno, Francesca Marino, Blen Kedir, Dan Wang, Saul A. Villeda, Tony Wyss-Coray, Dena B. Dubal
Journal: Nature Aging (2023)

Platelet factors regulate wound healing and can signal from the blood to the brain
The International Association for the Study of Lung Cancer Early Lung Imaging Confederation Open-Source Deep Learning and Quantitative Measurement Initiative
Authors: Stephen Lam, Murry W. Wynes, Casey Connolly, Kazuto Ashizawa, Sukhinder Atkar-Khattra, Chandra P. Belani, Domenic DiNatale, Claudia I. Henschke, Bruno Hochhegger, Claudio Jacomelli, Małgorzata Jelitto, Artit Jirapatnakul, Karen L. Kelly, Karthik Krishnan, Takeshi Kobayashi, Jacqueline Logan, Juliane Mattos, John Mayo, Annette McWilliams, Tetsuya Mitsudomi, Ugo Pastorino, Joanna Polańska, Witold Rzyman, Ricardo Sales dos Santos, Giorgio V. Scagliotti, Heather Wakelee, David F. Yankelevitz, John K. Field, James L. Mulshine, Ricardo Avila
Journal: Journal of Thoracic Oncology (2023)
Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency
Authors: Nigar Taghizade, Royala Babayeva, Altan Kara, Ibrahim Serhat Karakus, Mehmet Cihangir Catak, Alper Bulutoglu, Zehra Sule Haskologlu, Idil Akay Haci, Ceyda Tunakan Dalgic, Esra Karabiber, Sevgi Bilgic Eltan, Melek Yorgun Altunbas, Asena Pinar Sefer, Ahmet Sezer, Sefika Ilknur Kokcu Karadag, Elif Arik, Zuhal Karali, Aylin Ozhan Kont, Can Tuzer, Sait Karaman, Selver Seda Mersin, Nurhan Kasap, Enes Celik, Dilara Fatma Kocacik Uygun, Sezin Aydemir, Ayca Kiykim, Cigdem Aydogmus, Esra Ozek Yucel, Fatih Celmeli, Emrah Karatay, Emine Bozkurtlar, Semra Demir, Ayse Metin, Neslihan Edeer Karaca, Necil Kutukculer, Guzide Aksu, Sukru Nail Guner, Sevgi Keles, Ismail Reisli, Yasemin Kendir Demirkol, Tugba Arikoglu, Nesrin Gulez, Ferah Genel, Sara Sebnem Kilic, Caner Aytekin, Ozlem Keskin, Alisan Yildiran, Dilek Ozcan, Derya Ufuk Altintas, Fatma Omur Ardeniz, Esin Figen Dogu, Kamile Aydan Ikinciogullari, Elif Karakoc-Aydiner, Ahmet Ozen, Safa Baris
Journal: Journal of Allergy and Clinical Immunology (2023)
Gene editing of hematopoietic stem cells restores T-cell response in familial hemophagocytic lymphohistiocytosis
Authors: Viviane Dettmer-Monaco, Kristoffer Weißert, Sandra Ammann, Gianni Monaco, Lei Lei, Linda Gräßel, Manuel Rhiel, Julia Rositzka, Masako M. Kaufmann, Kerstin Geiger, Geoffroy Andrieux, Jessica Lao, Gudrun Thoulass, Christoph Schell, Melanie Boerries, Anna L. Illert, Tatjana I. Cornu, Stephan Ehl, Peter Aichele, Toni Cathomen
Journal: Journal of Allergy and Clinical Immunology (2023)
Reduced SARS-CoV-2 mRNA vaccine immunogenicity and protection in mice with diet-induced obesity and insulin resistance
Authors: Timothy R. O'Meara, Etsuro Nanishi, Marisa E. McGrath, Soumik Barman, Danica Dong, Carly Dillen, Manisha Menon, Hyuk-Soo Seo, Sirano Dhe-Paganon, Robert K. Ernst, Ofer Levy, Matthew B. Frieman, David J. Dowling
Journal: Journal of Allergy and Clinical Immunology (2023)

Obesity and type 2 diabetes mellitus (T2DM) are associated with an increased risk of severe outcomes from infectious diseases, including coronavirus disease 2019. These conditions are also associated with distinct responses to immunization, including an impaired response to widely used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines.
High-coverage genome of the Tyrolean Iceman reveals unusually high Anatolian farmer ancestry
Authors: Ke Wang, Kay Prüfer, Ben Krause-Kyora, Ainash Childebayeva, Verena J. Schuenemann, Valentina Coia, Frank Maixner, Albert Zink, Stephan Schiffels, Johannes Krause
Journal: Cell Genomics (2023)

The Tyrolean Iceman is known as one of the oldest human glacier mummies, directly dated to 3350–3120 calibrated BCE. A previously published low-coverage genome provided novel insights into European prehistory, despite high present-day DNA contamination. Here, we generate a high-coverage genome with low contamination (15.3×) to gain further insights into the genetic history and phenotype of this individual. Contrary to previous studies, we found no detectable Steppe-related ancestry in the Iceman. Instead, he retained the highest Anatolian-farmer-related ancestry among contemporaneous European populations, indicating a rather isolated Alpine population with limited gene flow from hunter-gatherer-ancestry-related populations. Phenotypic analysis revealed that the Iceman likely had darker skin than present-day Europeans and carried risk alleles associated with male-pattern baldness, type 2 diabetes, and obesity-related metabolic syndrome. These results corroborate phenotypic observations of the preserved mummified body, such as high pigmentation of his skin and the absence of hair on his head.